EP0310260A2 - Platin-Komplex und dessen Verwendung als Anti-Tumor-Agenzien - Google Patents

Platin-Komplex und dessen Verwendung als Anti-Tumor-Agenzien Download PDF

Info

Publication number
EP0310260A2
EP0310260A2 EP88308469A EP88308469A EP0310260A2 EP 0310260 A2 EP0310260 A2 EP 0310260A2 EP 88308469 A EP88308469 A EP 88308469A EP 88308469 A EP88308469 A EP 88308469A EP 0310260 A2 EP0310260 A2 EP 0310260A2
Authority
EP
European Patent Office
Prior art keywords
cis
platinum
compound
water
sulfato
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP88308469A
Other languages
English (en)
French (fr)
Other versions
EP0310260A3 (de
Inventor
Seiichi Nishi
Kazuo Ohishi
Kunisuke Izawa
Tsuyoshi Shiio
Tetsuo Suami
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ajinomoto Co Inc
Original Assignee
Ajinomoto Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ajinomoto Co Inc filed Critical Ajinomoto Co Inc
Publication of EP0310260A2 publication Critical patent/EP0310260A2/de
Publication of EP0310260A3 publication Critical patent/EP0310260A3/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to novel, water-soluble platinum complexes of cis-diaminocyclohexanol or cis­diaminocyclohexane, and to anti-tumor agents containing the same.
  • Cisplatin cis­dichlorodiamineplatinum(II)
  • Cisplatin cis­dichlorodiamineplatinum(II)
  • platinum(II) complex of cisdichloro-1,2-diaminocyclohexane was found to be a promising compound [Chem. Biol. Interactions, 5 , 415 (1972)], but a problem involved in this substance is the low solubility in water.
  • platinum complexes of cis-diaminocyclohexanol and cis-diaminocyclohexane represented by any one of the following general formulas.
  • X2 denotes a radical represented by any one of the following structural formulas
  • R1 to R8 are each hydrogen or hydroxyl, provided that at least one of these is hydroxyl, and there is not more than one hydroxyl on each carbon atom constituting the cyclohexane ring
  • R9 is hydrogen, hydroxyl, lower alkyl (of 1 to 5 carbon atoms), or phenyl
  • R10 is hydrogen, hydroxyl, amino which may optionally be substituted (for example, dimethylamino, N-acetylamino, piperidyl and pyrrolidyl group), lower alkyl (of 1 to 5 carbon atoms), a lower alkoxy (of 1 to 5 carbon atoms), phenyl, or phenoxy; with the
  • sulfates may be prepared by mixing a cis-dichloro-diaminocyclo­hexanolplatinum(II), or a cis-dichloro-1,3-diaminocyclohex­aneplatinum(II), with silver sulfate, filtering off the silver chloride thus formed, concentrating the filtrate, and adding ethanol to the concentrate.
  • Salts of organic acids may be prepared by mixing a cis­dichloro-diaminocyclohexanolplatinum(II), or a cis­dichloro-1,3-diaminocyclohexaneplatinum(II), with silver nitrate, filtering off the silver chloride thus formed, adding an organic acid (such as oxalic, glycolic and cyclobutane-1,1-dicarboxylic acids ) to the filtrate, neutralizing the mixture with caustic soda, allowing the resulting solution to stand, collecting the precipitate thus formed, and purifying it by known techniques (e.g., re­crystallization and treatment with activated charcoal ).
  • an organic acid such as oxalic, glycolic and cyclobutane-1,1-dicarboxylic acids
  • the starting material cis-dichloro-diaminocyclohexanol­platinum(II) can be easily obtained by adding an aqueous solution of a diaminocyclohexanol hydrochloride ( or hydro­bromide ) to an aqueous solution of potassium chloro­platinate, neutralizing the reaction mixture with sodium bicarbonate, allowing the resulting solution to stand in a refrigerator, and collecting the crystals thus formed by filtration, followed by washing.
  • Diaminocyclohexanols can be synthesized according to the method reported by some of the present inventors [ Bull. Chem. Soc.
  • cis-dichloro-1,3-­diaminocyclohexaneplatinum(II) can also be prepared by the reaction of 1,3-diaminocyclohexane and potassium chloro­platinate in the same manner as above.
  • the new platinum complexes thus obtained are used as an anti-tumor agent, for example, in the form of a suspension.
  • the suitable unit dose of active ingredient is in the range of 0.01 to 2000 mg ( a total of 0.02 to 500 mg a day ). This amount may be properly changed within the above range depdending on the severity of disease, body weight of patient and other factors generally accepted by those skilled in the art.
  • a compound of this invention is mixed with physiolog­ically acceptable additives, (such as a vehicle, carrier, excipient, binder, preservative, stabilizer and perfume ), and fabricated into commonly used dosage forms so that each unit dose will contain the active ingredient in an amount of about 0.02 to 500 mg.
  • physiolog­ically acceptable additives such as a vehicle, carrier, excipient, binder, preservative, stabilizer and perfume
  • Parenteral injections can be prepared by dissolving or suspending the active ingredient in sterile water together with a vegetable oil (e.g., seasame oil, coconut oil, peanut oil and cottonseed oil ) or a synthetic oily vehicle (e.g., ethyl oleate ), and, as required, a buffering agent, preservative, antioxidant and other additives.
  • a vegetable oil e.g., seasame oil, coconut oil, peanut oil and cottonseed oil
  • a synthetic oily vehicle e.g., ethyl oleate
  • the reaction mixture was concentrated, the residue was dissolved in 2 ml water, 10 ml ethanol was added to the solution, and the mixture was kept cooled in ice for three hours. The faint-yellow precipitate which separated out was collected by filtration, washed with ethanol and dried, giving 270 mg ( yield: 31 % ) of the product.
  • This compound ( 760 mg ) was mixed with 680 mg silver nitrate and 12 ml water, and the mixture was heated in a dark place with stirring at 60 to 65°C for three hours. The reaction mixture was filtered, the precipitate on the filter was washed with water, and the washings were added to the filtrate. To the combined solution, was added 12 ml of 0.2M aqueous solution of disodium oxalate ( prepared by neutralizing oxalic acid dihydrate with 30% caustic soda solution to pH 6 ), and the mixture was stirred overnight at room temperature.
  • reaction mixture was treated with activated charcoal and concentrated, the residue was dis­solved in 2 ml water, 10 ml ethanol was added to the solution, and the mixture was kept cooled in ice for about three hours.
  • the white precipitate which separated out was collected by filtration, washed with ethanol and dried, giving 334 mg ( yield: 42 % ) of the product.
  • mice of 5-week age were used as test animals ( five head for each group ).
  • Sarcoma-180 cells ( 1 x 106 ) were intraperitoneally transplanted to each of the test animals, each of the Pt(II) complexes listed in Table 1 was then injected intraperi­toneally on the next day, and the life-prolonging rate was measured for each test group.
  • Physiologically saline was used as the solvent of injections.
  • Table 1 show the excellent anti-tumor activity of the platinum complexes of this invention.
  • Table 1 Life-prolonging Rate (%) Compound No. Dose ( mg/Kg x 1 ) 4.0 8.0 16.0 32.0 1 189 218 266 2 295 532 534 3 212 182 252 4 248 258 364 5 202 187 236 6 126 106 7 126 120 241
  • mice of 5-week age were used as test animals ( five head for each group ).
  • L1210 cells ( 1 x 105 ) were intraperitoneally trans­planted to each of the test animals, each of the Pt(II) complexes listed in Table 2 was then injected intraperi­toneally one day, five days and nine days after transplan­tation ( a total of three times ), and the life-prolonging rate was measured for each test group.
  • Physiological saline was used as the solvent of injections.
  • Table 2 Life-prolonging Rate (%) Compound No. Dose ( ⁇ mol/Kg x 3 ) 7.5 15.0 30.0 60.0 1 115 115 132 2 136 134 151 3 116 122 147 4 127 222 245 5 121 189 155 6 98 104 7 102 109 119
  • mice of 5-week age were used as test animals ( five head for each group ).
  • Colon38 cells ( 40 mg ) were subcutaneously trans­planted to each of the test animals at the haunch, each of the Pt(II) complexes listed in Table 3 was then injected intraperitoneally 1 day, 8 days and 15 days after transplan­ tation ( a total of three times ), and the tumor-growth inhibition rate was measured for each test group 21 days afeter transplantation.
  • Table 3 Tumor-growth Inhibition Rate (%) Compound No. Dose ( ⁇ mol/Kg x 3 ) 20.0 30.0 45.0 1 24 16 45 2 47 78 97 3 70 72 96 4 54 77 88 5 36 56 56
  • L1210 cells and Cisplatin-resistant L1210 cells under subcultivation were incubated in RPMI1640 medium containing 10% fetal bovine serum at 37°C for 46 hours in an atmosphere containing 5% carbon dioxide.
  • [3H]-thymidine was added to the grown cells, and incubation was continued for an additional two hours.
  • the growth inhibition rate of a drug was calculated from the amounts of [3H]-thymidine taken into the cells in the presence and absence of that drug, and the 50% growth inhibition concentration ( IC50 ) was determined from the graph of inhibition rate plotted against drug concentration.
  • the degree of drug resistance was calculated from the ratio of IC50 for Cisplatin-resistant L1210 cells to that for L1210 cells.
  • Table 4 Compound No. IC 50 (L1210 cells) ( ⁇ M) IC 50 (resistant cells) ( ⁇ M) Degree of Resistance Cisplatin 1.0 10.5 10.5 1 3.5 6.6 1.9 2 1.7 3.2 1.9 3 1.3 2.5 1.9 4 2.4 5.0 2.1 5 3.1 7.9 2.5
  • mice of 5-week age were used as test animals ( eight head for each group ).
  • Colon 38 cells ( 40 mg ) were subcutaneously transplated to each of the test animals at the haunch, each of the Pt(II) complexes listed in Table 5 was then injected intravenously 1 day, 5 days, 9 days, 12 days, 16 days and 20 days after transplantation ( a total of 6 times ), and the tumor-growth inhibition rate was measured for each test group 21 days after transplantation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP19880308469 1987-09-26 1988-09-14 Platin-Komplex und dessen Verwendung als Anti-Tumor-Agenzien Withdrawn EP0310260A3 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP241720/87 1987-09-26
JP24172087 1987-09-26
JP211695/88 1988-08-26
JP63211695A JPH01156990A (ja) 1987-09-26 1988-08-26 新規白金錯体及びその用途

Publications (2)

Publication Number Publication Date
EP0310260A2 true EP0310260A2 (de) 1989-04-05
EP0310260A3 EP0310260A3 (de) 1991-12-11

Family

ID=26518790

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19880308469 Withdrawn EP0310260A3 (de) 1987-09-26 1988-09-14 Platin-Komplex und dessen Verwendung als Anti-Tumor-Agenzien

Country Status (3)

Country Link
US (1) US5041579A (de)
EP (1) EP0310260A3 (de)
JP (1) JPH01156990A (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106469A1 (de) * 2002-06-14 2003-12-24 Faustus Forschungs Cie. Translational Cancer Research Gmbh Tumorhemmende platin(ii)-oxalato-komplexe

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0464210A4 (en) * 1989-12-15 1992-11-25 Tsumura & Co. Novel platinum complex and antitumor drug containing the same as active ingredient
JPH09507233A (ja) * 1993-12-29 1997-07-22 マトリクス ファーマスーティカル，インコーポレイティド 細胞増殖性疾患に罹る宿主の治療方法及び治療のための組成物
AUPQ641100A0 (en) * 2000-03-23 2000-04-15 Australia Nuclear Science & Technology Organisation Methods of synthesis and use of radiolabelled platinum chemotherapeutic ag ents

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0098135A2 (de) * 1982-06-28 1984-01-11 Engelhard Corporation Lösliche Platin(II)-Komplexe
EP0186085A2 (de) * 1984-12-17 1986-07-02 American Cyanamid Company Platin-Komplexe
JPS61286396A (ja) * 1985-06-12 1986-12-16 Ajinomoto Co Inc 新規白金錯体およびその用途
EP0232785A1 (de) * 1986-01-31 1987-08-19 American Cyanamid Company Hydroxylierte 1,2-Diamincyclohexan Platinkomplexe
JPS62190192A (ja) * 1986-02-17 1987-08-20 Nippon Kayaku Co Ltd 新規白金錯体

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4786725A (en) * 1982-06-28 1988-11-22 Engelhard Corporation Solubilized platinum (II) complexes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0098135A2 (de) * 1982-06-28 1984-01-11 Engelhard Corporation Lösliche Platin(II)-Komplexe
EP0186085A2 (de) * 1984-12-17 1986-07-02 American Cyanamid Company Platin-Komplexe
JPS61286396A (ja) * 1985-06-12 1986-12-16 Ajinomoto Co Inc 新規白金錯体およびその用途
EP0232785A1 (de) * 1986-01-31 1987-08-19 American Cyanamid Company Hydroxylierte 1,2-Diamincyclohexan Platinkomplexe
JPS62190192A (ja) * 1986-02-17 1987-08-20 Nippon Kayaku Co Ltd 新規白金錯体

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 106, no. 6, 9th February 1987, page 677, abstract no. 42856w, Columbus, Ohio, US; Y. QU et al.: "Synthesis, characterization and antitumor activity of platinum complexes of 1,3-diaminocyclohexane", & YINGYONG HUAZUE 1986, 3(3), 25-9 *
PATENT ABSTRACTS OF JAPAN, vol. 11, no. 159 (C-432)(2606), 22nd May 1987; & JP-A-61 286 396 (AJINOMOTO CO., INC.) 16-12-1986 *
PATENT ABSTRACTS OF JAPAN, vol. 12, no. 40 (C-474)(2887), 5th February 1988; & JP-A-62 190 192 (NIPPON KAYAKU CO., LTD) 20-08-1987 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106469A1 (de) * 2002-06-14 2003-12-24 Faustus Forschungs Cie. Translational Cancer Research Gmbh Tumorhemmende platin(ii)-oxalato-komplexe
US7057059B2 (en) 2002-06-14 2006-06-06 Faustus Forschungs Cie. Translational Cancer Research Gmbh Tumor-inhibiting platinum (II) oxalate complexes

Also Published As

Publication number Publication date
EP0310260A3 (de) 1991-12-11
JPH01156990A (ja) 1989-06-20
US5041579A (en) 1991-08-20

Similar Documents

Publication Publication Date Title
EP0155705B1 (de) Antitumor-Platin-Komplexe
JP2710654B2 (ja) １、２−ビス（アミノメチル）シクロブタン−白金錯化合物、その製造方法、該化合物を含有する抗腫瘍作用を有する薬剤およびその製造方法
EP0219936B1 (de) Platinkomplexe
EP0166366B1 (de) Platinkomplexe
US5434256A (en) Diamine platinum complexes as antitumor agents
PH26424A (en) Platinum pharmaceutical agents
US5318962A (en) Water soluble 1,2-diaminocyclohexane platinum (IV) complexes as antitumor agents
KR910009823B1 (ko) 백금착물(白金錯物)
JPH01294683A (ja) 新規白金錯体および該化合物を有効成分とする抗腫瘍剤並びに該化合物製造用中間体
US5393909A (en) Diamine platinum complexes as antitumor agents
EP0163316B1 (de) Platin-Intercalativ-Komplexe zur Behandlung von Krebs
US4739087A (en) Antineoplastic platinum complexes
EP0176005B1 (de) Platinkomplexe
EP0310260A2 (de) Platin-Komplex und dessen Verwendung als Anti-Tumor-Agenzien
US5028726A (en) Platinum amine sulfoxide complexes
JPH0735390B2 (ja) 抗腫瘍性白金化合物
EP0357108A2 (de) Platin(IV)-diamin-Komplex, Verfahren zur Herstellung dieser Verbindung, Zusammensetzung mit Antitumorwirkung, die mindestens eine Platin-Verbindung enthält, und geformte Zusammensetzung mit Antitumorwirkung
US5008419A (en) Novel platinum complex
EP0357109B1 (de) Platin-(II)-diamin-Komplex, Verfahren zur Herstellung dieser Verbindung, Zusammensetzung mit Antitumorwirkung, die mindestens eine Platin-Verbindung enthält, und geformte Zusammensetzung mit Antitumorwirkung
EP0423707A2 (de) Platinkomplexe
KR890004351B1 (ko) 항 종양성 백금 착체의 제조방법
US5616613A (en) Platinum(II) complex and malignant tumor treatment agent
EP0518645B1 (de) Platin(II)-Komplex und Antitumormittel
EP0308910A2 (de) Platin-Komplex
US4999444A (en) Novel neutral mixed ligand platinum(II) and platinum(IV) complexes

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): DE FR GB IT

17P Request for examination filed

Effective date: 19901103

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): DE FR GB IT

PUAF Information related to the publication of a search report (a3 document) modified or deleted

Free format text: ORIGINAL CODE: 0009199SEPU

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

D17D Deferred search report published (deleted)
AK Designated contracting states

Kind code of ref document: A3

Designated state(s): DE FR GB IT

17Q First examination report despatched

Effective date: 19921109

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19940125